EP0948496A2 - Substituted pyrimidinone and pyridone compounds and methods of use - Google Patents

Substituted pyrimidinone and pyridone compounds and methods of use

Info

Publication number
EP0948496A2
EP0948496A2 EP97951678A EP97951678A EP0948496A2 EP 0948496 A2 EP0948496 A2 EP 0948496A2 EP 97951678 A EP97951678 A EP 97951678A EP 97951678 A EP97951678 A EP 97951678A EP 0948496 A2 EP0948496 A2 EP 0948496A2
Authority
EP
European Patent Office
Prior art keywords
radicals
amino
alkyl
alkoxy
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97951678A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ulrike D. Spohr
Michael J. Malone
Nathan B. Mantlo
Jeff A. Zablocki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Original Assignee
Amgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amgen Inc filed Critical Amgen Inc
Publication of EP0948496A2 publication Critical patent/EP0948496A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention comprises a new class of compounds useful in treating diseases, such as TNF- ⁇ , IL-l ⁇ , IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes.
  • diseases such as TNF- ⁇ , IL-l ⁇ , IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes.
  • the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation.
  • This invention also relates to intermediates and processes useful in the preparation of such compounds .
  • Interleukin-1 IL-1
  • Tumor Necrosis Factor ⁇ TNF- ⁇
  • IL-1 Interleukin-1
  • TNF- ⁇ Tumor Necrosis Factor ⁇
  • IL-1 and TNF- ⁇ are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g., lipopolysaccharide - LPS) or external cellular stress (e.g., osmotic shock and peroxide).
  • inflammatory stimuli e.g., lipopolysaccharide - LPS
  • external cellular stress e.g., osmotic shock and peroxide
  • Elevated levels of TNF- ⁇ and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic ⁇ cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome
  • ARDS psoriasis
  • Crohn's disease psoriasis
  • allergic rhinitis ulcerative colitis
  • anaphylaxi ⁇ contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection.
  • TNF- ⁇ plays a role in head trauma, stroke, and ischemia.
  • TNF- ⁇ levels increased in the contused hemisphere (Shohami et al . , J " . Cereb . Blood Flow Metab. 14, 615 (1994)).
  • TNF- ⁇ mRNA of TNF- ⁇ increased (Feurstein et al . , Neurosci . Lett . 164, 125 (1993)).
  • Administration of TNF- ⁇ into the rat cortex has been reported to result in significant neutrophil accumulation in capillaries and adherence in small blood vessels.
  • TNF- ⁇ promotes the infiltration of other cytokines (IL-l ⁇ , IL-6) and also chemokines , which promote neutrophil infiltration into the infarct area
  • TNF- ⁇ has also been implicated to play a role in type II diabetes
  • TNF- ⁇ appears to play a role in promoting certain viral life cycles and disease states associated with them.
  • TNF- ⁇ secreted by monocytes induced elevated levels of HIV expression in a chronically infected T cell clone (Clouse et al . , J. Immunol . 142, 431 (1989)).
  • Lahdevirta et al . (Am . J. Med. 85, 289 (1988)) discussed the role of TNF- ⁇ in the HIV associated states of cachexia and muscle degradation.
  • TNF- ⁇ is upstream in the cytokine cascade of inflammation.
  • TNF- ⁇ may lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-1, IL-6, and IL-8.
  • Elevated levels of IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis; anaphylaxis ; muscle degeneration; cachexia;
  • Viruses sensitive to TNF- ⁇ inhibition e.g., HIV-1, HIV-2, HIV-
  • TNF- ⁇ and IL-1 appear to play a role in pancreatic ⁇ cell destruction and diabetes.
  • Pancreatic ⁇ cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic ⁇ cells often accompanies type I diabetes. Pancreatic ⁇ cell functional abnormalities may occur in patients with type II diabetes. Type II diabetes is characterized by a functional resistance to insulin. Further, type II diabetes is also often accompanied by elevated levels of plasma glucagon and increased rates of hepatic glucose production.
  • Glucagon is a regulatory hormone that attenuates liver gluconeogenesis inhibition by insulin. Glucagon receptors have been found in the liver, kidney and adipose tissue.
  • glucagon antagonists are useful for attenuating plasma glucose levels (WO 97/16442, incorporated herein by reference in its entirety) .
  • antagonizing the glucagon receptors it is thought that insulin responsiveness in the liver will improve, thereby decreasing gluconeogenesis and lowering the rate of hepatic glucose production.
  • IL-1 chemokines
  • IL-8 chemokines
  • adhesion molecules adhesion molecules
  • IL-1 also appears to play a role in promoting certain viral life cycles.
  • cytokine- induced increase of HIV expression in a chronically infected macrophage line has been associated with a concomitant and selective increase in IL-1 production (Folks et al . , J “ . Immunol . 136, 40 (1986)). Beutler et al . (J " . Immunol .
  • IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis .
  • IL-8 also has the ability to activate neutrophils.
  • reduction in IL- 8 levels may lead to diminished neutrophil infiltration.
  • TNF- ⁇ Several approaches have been taken to block the effect of TNF- ⁇ .
  • TNF- ⁇ soluble receptors for TNF- ⁇
  • TNFR-55 or TNFR-75 soluble receptors for TNF- ⁇
  • cA2 monoclonal antibody specific to TNF- ⁇
  • EP 4814408 incorporated herein by reference in its entirety, describes pyrimidinone compounds useful as angiotensin II antagonists wherein one of the pyrimidinone ring nitrogen atoms is substituted with a substituted phenyl, phenylmethyl or phenethyl radical.
  • CA 2,020,370 incorporated herein by reference in its entirety, describes pyrimidinone compounds useful as angiotensin II antagonists wherein one of the pyrimidinone ring nitrogen atoms is substituted with a substituted biphenylaliphatic hydrocarbon radical.
  • the present invention comprises a new class of compounds useful in the prophylaxis and treatment of diseases, such as TNF- ⁇ , IL-l ⁇ , IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes.
  • diseases such as TNF- ⁇ , IL-l ⁇ , IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes.
  • the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation.
  • the invention also comprises pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of TNF- ⁇ , IL-l ⁇ , IL-6 and/or IL-8 mediated diseases, such as inflammatory, pain and diabetes diseases, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
  • X is 0, S or NR 5 ; preferably, X is 0 or S; and most preferably, X is 0;
  • U is NR 21 or CHR 21 ; preferably, U is NR 21 ;
  • n is an integer of 1-3;
  • R l and R2 are each independently -Y or -Z-Y, and R 3 and R 4 are each independently -Z-Y; provided that R 4 is other than a substituted-aryl, (substituted-aryl) methyl or (substituted-aryl) ethyl radical, and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each -Y and -Z-Y is 0-3; preferably, 0-2; more preferably, 0-1;
  • R 2 is a radical of hydrogen, C1-C 4 alkyl, halo, cyano, hydroxy, C1-C 4 alkoxy, C1-C 2 haloalkoxy of 1-3 halo radicals, C 1 -C4 alkylthio, amino, C1-C 4 alkylamino, di-(C ⁇ -C 4 alkyl) amino or C 1 -C 2 haloalkyl of 1-3 halo radicals; more preferably, R 2 is a radical of hydrogen, C 1 -C 4 alkyl, halo, cyano, hydroxy, C 1 -C 4 alkoxy, trifluoromethoxy or trifluoromethyl; most preferably, R 2 is a hydrogen radical;
  • R 3 is a hydrogen radical or (1) Ci-Cs alkyl or C2-C 8 alkenyl radical optionally substituted by (a) 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (C 1 -C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (C1-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C1-C4 alkoxy) carbonyla ino, C1-C4 alkylsulfony
  • R3 is a hydrogen radical or
  • Ci-Ce alkyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals; or
  • aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals ;
  • R3 is a radical of hydrogen or C1-C4 alkyl; more preferably, R3 is a hydrogen, methyl or ethyl radical; preferably, R4 is
  • C. L -C8 alkyl or C2-C8 alkenyl radical optionally substituted by (a) 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-
  • heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals;
  • R4 is
  • C1-C8 alkyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals; or
  • R4 is a C 1 -C 4 alkyl radical; most preferably, R 4 is a methyl or ethyl radical;
  • alkyl, alkenyl or alkynyl radical optionally substituted by (a) 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, halo, alkyl or haloalkyl;
  • heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or
  • aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl;
  • each Z is independently a
  • each Z is independently a (1) Ci-C ⁇ alkyl, C2-C8 alkenyl or C 2 -C 8 alkynyl radical optionally substituted by (a) 1-3 radicals of amino, Ci- C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C ⁇ -C 4 alkyl) amino, C1-C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkyl radical optional
  • aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C1-C4 alkylthio, cyano, halo, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals;
  • each Z is independently a (1) Ci-C ⁇ alkyl or C2-C8 alkenyl radical optionally substituted by (a) 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C ⁇ C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (C1-C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, halo, C 1 -C4 alky
  • heterocyclyl radical optionally substituted by 1-2 radicals of amino, di- (C 1 -C4 alkyl) amino, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkyl radicals; or (3) aryl or heteroaryl radical optionally substituted by
  • each Z is independently a
  • C1-C4 alkyl or C2-C5 alkenyl radical optionally substituted by (a) 1-3 radicals of amino, di- (C1-C2 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C2 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl or trifluoromethyl radicals ;
  • heterocyclyl radical optionally substituted by 1-2 radicals of amino, di- (C1-C2 alkyl) amino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio or C1-C4 alkyl radicals; or
  • aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di- (C1-C2 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, Ci- C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
  • each Z is independently a (1) C1-C4 alkyl or C2-C5 alkenyl radical optionally substituted by (a) 1-3 radicals of amino, di- (C1-C2 alkyl) amino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio or halo, and (b) 1-2 radicals of aryl or heteroaryl optionally substituted by 1-2 radicals of amino, di- (C1-C2 alkyl) amino, acetamido,
  • aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di- (C1-C2 alkyl) amino, acetamido, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
  • each Z is independently a C1-C4 alkyl radical optionally substituted by 1-2 radicals of amino, di-(C ⁇ -C2 alkyl) amino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo or aryl or heteroaryl optionally substituted by 1-2 radicals of hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo, C1-C4 alkyl or trifluoromethyl radicals; and
  • each Z is independently a C1-C4 alkyl radical optionally substituted by 1-2 radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio or halo radicals;
  • each Y is independently a
  • each Y is independently a
  • each Y is independently a
  • each Y is independently a (1) hydrogen radical; (2) -C(0)-R 2 o radical;
  • each Y is independently a
  • each Y is independently a -OR21, -SR21 or -NR5R21 radical;
  • each R5 is independently (1) hydrogen radicals
  • alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, -S0 3 H or halo; or (3) aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl;
  • each R 5 is independently
  • each R 5 is independently (1) hydrogen radicals
  • each R 5 is independently (1) hydrogen radicals; (2) C 1 -C 4 alkyl or C 2 -C 5 alkenyl radicals optionally substituted by 1-3 radicals of amino, di-(C ⁇ -C 4 - alkyl) amino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, - SO 3 H or halo; or (3) phenyl-C ⁇ -C 2 -alkyl , heteroaryl-C ⁇ -C 2 -alkyl, heterocyclyl-C ⁇ -C2-alkyl or C 3 -C 6 -cycloalkyl-C ⁇ -C 2 -alkyl radicals optionally substituted by 1-3 radicals of amino, di- (C ⁇ C 4 -alkyl) amino, hydroxy, C 1 -C 4 alkoxy, Ci- C alkylthio, C1-C4 alkyl or C 1 -C2 haloalkyl of 1-3 halo radicals;
  • each R 5 is independently
  • C 1 -C 4 alkyl radical optionally substituted by 1-3 radicals of amino, di- (C ⁇ -C2-alkyl) amino, hydroxy, C1-C 2 alkoxy, C 1 -C 2 alkylthio or halo; or
  • each R 5 is independently (1) hydrogen radical
  • each R 5 is independently hydrogen or C 1 -C 4 alkyl radical; and most preferably, each R 5 is a hydrogen radical; wherein each R2 0 is independently
  • alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N- (alkoxycarbonyl ) -N- (alkyl ) amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo or aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1- 3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkanoyl, hydroxy, alkoxy, alkylthio
  • each R20 is independently
  • heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
  • aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C ⁇ -C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy) carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
  • each R20 is independently
  • heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
  • aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4 alkoxy) carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or C1-C4 haloalkyl of 1- 3 halo radicals;
  • each R20 is independently
  • C1-C8 alkyl or C2-C5 alkenyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C ⁇ -C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, N- ( (C1-C4 alkoxy) carbonyl) -N- (C1-C4 alkyl) amino, aminocarbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo or aryl-C ⁇ -C4-alkoxy, aryl-C ⁇ -C4- alkylthio, aryl-C ⁇ -C4-alkylsulfonyl, C 3 -C6 cycloalkyl, heterocyclyl, aryl or
  • heterocyclyl radical optionally substituted by 1-2 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkyl; or
  • aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, (C 1 -C 4 alkoxy) carbonyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or C1-C 2 haloalkyl of 1-3 halo radicals;
  • each R2 0 is independently
  • Ci-C ⁇ alkyl or C2-C5 alkenyl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C ⁇ -C4 alkyl) amino, C1-C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, N- ( (C 1 -C 4 alkoxy) carbonyl) -N- (C1-C 4 alkyl) amino, aminocarbonylamino, hydroxy, C1-C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C1-C 4 alkylsulfonyl, halo or aryl-C ⁇ -C 4 -alkoxy, aryl-C ⁇ -C 4 - alkylthio, aryl-C ⁇ -C 4 -alkylsulfonyl, C 3 -C 6 cycloalkyl, heterocycl
  • each R20 is independently independently selected from the group consisting of: hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, C 1 -C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, acetamido, (C 1 -C 4 alkoxy) carbonylamino, C ⁇ C 4 alkylsulfonylamino, (C 1 -C 4 alkoxy) carbonyl , hydroxy, C 1 -C 4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or trifluoromethyl radicals; more preferably, each R20 is independently
  • C1-C8 alkyl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, N- ( (C1-C4 alkoxy) carbonyl) -N- (C1-C4 alkyl) amino, aminocarbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo or C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1- 2 radicals of amino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino,
  • heterocyclyl radical optionally substituted by 1-2 radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or C1- C4 alkyl ; or
  • aryl or heteroaryl radicals optionally substituted by 1-2 radicals of (C1-C4 alkoxy) carbonyl, amino, C1-C4 alkylamino, di-(C ⁇ -C4 alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or trifluoromethyl radicals;
  • each R20 is independently
  • Ci-C ⁇ alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, t- butoxycarbonylamino , N- ( ( t-butoxy) carbonyl ) -N- (methyl) amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; (2) heterocyclyl radical optionally substituted by 1-2 radicals of hydroxy or C 1 -C 4 alkyl; or
  • aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;
  • each R 2 0 is independently
  • C 1 -C 6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, t- butoxycarbonylamino , N- ( ( t-butoxy) carbonyl ) -N- (methyl) amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C 5 -C 6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;
  • heterocyclyl radical or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;
  • each R20 is independently
  • C 1 -C 6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, hydroxy or phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;
  • each R 21 is independently hydrogen radical or R 20 ;
  • each R 22 is independently ( 1 ) hydrogen radical ; (2) alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or
  • heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; provided when Z is a bond and Y is -NR 22 - C(0)-NH 2 , then R 22 is other then an optionally substituted aryl radical;
  • each R 2 2 is independently
  • C 1 -C 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C ⁇ -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C1-C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; or (3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di
  • each R2 2 is independently (1) hydrogen radical;
  • C1-C 4 alkyl radical optionally substituted by a radical of phenyl or heteroaryl optionally substituted by 1-3 radicals of amino, di-(C ⁇ -C 2 alkyl) amino, C1-C 5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, Ci- C 4 alkoxy, C1-C4 alkylthio, cyano, halo, C 1 -C 4 alkyl or C 1 -C 2 haloalkyl of 1-3 halo radicals;
  • each R 22 is independently hydrogen or C1-C 4 alkyl radical; and most preferably, each R 22 is independently hydrogen or methyl radical;
  • R ll and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of ( 1 ) R30; (2) halo or cyano radicals;
  • Rn is other than a 4-pyridyl, 4- pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and (2) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of Rn and R 12 is 0-1; preferably, Rn and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of (1) R30;
  • Rn is other than a 4-pyridyl, 4- pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and (2) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of Rn and R12 is 0-1;
  • Rn and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of
  • Rn is an aryl radical and R12 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of ( 1 ) R30 ;
  • Rn is an aryl radical and R 2 is a heteroaryl radical , wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of
  • Rn is an aryl radical optionally substituted by 1-2 radicals of (1) R 30 ; (2) halo or cyano radicals; or (3) -C (0) -NR 31 R 32 , -OR 29 , -SR 29 , - S(O)-R 30 , -S(O) 2 -R30, -S(0) 2 -NR3iR 32 , -NR31R32 or -NR33- C(0)-R 29 radicals; more preferably, Rn is an aryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl , methyl or trifluoromethyl radicals; more preferably, Rn is an unsubstituted phenyl or naphthyl radical or a phenyl radical substituted by 1-2 radicals of
  • each R 3 0 is independently
  • alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of -NR31R31, -CO2R2 3 hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl;
  • heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or
  • aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl ;
  • each R30 is independently (1) C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl radicals optionally substituted by 1-3 radicals of -NR31R31, - CO2R23- hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo or aryl- C ⁇ -C4-alkoxy, aryl-C ⁇ -C4-alkylthio, aryl-C ⁇ C4- alkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C
  • heterocyclyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C ⁇ C4 haloalkyl of 1-3 halo radicals; or
  • aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals;
  • each R30 is independently
  • each R30 is independently
  • aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
  • each R30 is independently
  • C1-C4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di- (C1-C2 alkyl) amino, acetamido, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or trifluoromethyl radicals;
  • aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, di-(C ⁇ -C2 alkyl) amino, acetamido, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or trifluoromethyl radicals;
  • each R30 is independently
  • R30 is independently
  • C1-C4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;
  • each R29 is independently hydrogen radical or R30; and most preferably, R29 is an aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;
  • each R31 is independently
  • alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;
  • each R31 is independently
  • C1-C4 alkyl radical optionally substituted by an C3- C ⁇ cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C1-C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or (3) aryl, heteroaryl, heterocyclyl or C3-C8 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoy
  • each R31 is independently
  • each R31 is independently hydrogen or C1-C4 alkyl radicals; and most preferably, each R31 is independently hydrogen, methyl or ethyl radicals;
  • each R32 is independently
  • alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or
  • aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;
  • each R32 is independently (1) hydrogen radicals; (2) C1-C 4 alkyl radical optionally substituted by an C 3 - C ⁇ cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C ⁇ -C4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; or
  • aryl, heteroaryl, heterocyclyl or C 3 -C 8 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C 1 -C4 alkylamino, di- (C1-C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C1-C4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals;
  • each R 32 is independently
  • C 1 -C 4 alkyl radical optionally substituted by an C 3 - Ce cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; or (3) aryl, heteroaryl, heterocyclyl or C 3 -C 6 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C1-C 4 alkylamino, di- (C 1 -C 4 alkyl) amino
  • each R 32 is independently (1) hydrogen radicals; (2) C1-C4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di-(C ⁇ -C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl or trifluoromethyl radicals; or
  • phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C1-C4 alkylamino, di- (C1-C4 alkyl) amino, C1-C5 alkanoylamino, (C1-C4 alkoxy) carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl or trifluoromethyl radicals;
  • each R 3 2 is independently
  • R32 is independently (1) hydrogen or C1-C4 alkyl radical; or
  • alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;
  • each R 33 is independently
  • C 1 -C 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C ⁇ -C 4 alkyl) amino, C1-C5 alkanoylamino, (C1-C 4 alkoxy) carbonylamino, C1-C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C4 alkylthio, cyano, C 1 -C 4 alkyl or Ci- C 4 haloalkyl of 1-3 halo radicals;
  • each R 33 is independently hydrogen or C 1 -C 4 alkyl radical; and most preferably, each R 33 is independently hydrogen or methyl radical .
  • the compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers .
  • Compounds of interest include the following:
  • R 11 , R 12 , and R 1 are one of the combinations given in the following table:
  • R 11 , R 12 , and R 1 are one of the combinations given
  • R 11 , R 12 , and R 1 are one of the combinations given
  • R 2 is H, methyl or benzyl
  • R 11 , R 12 , and R 1 are one of the combinations given in the following table:
  • Alkyl alone or in combination, means a straight-chain or branched-chain alkyl radical containing preferably 1- 15 carbon atoms (C 1 -C 15 ) , more preferably 1-8 carbon atoms (Ci-C ⁇ ) / even more preferably 1-6 carbon atoms (C 1 -C 6 ) , yet more preferably 1-4 carbon atoms (C 1 -C 4 ) , still more preferably 1-3 carbon atoms (C 1 -C 3 ) , and most preferably 1-2 carbon atoms (C 1 -C 2 ) •
  • radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like.
  • Hydroalkyl alone or in combination, means an alkyl radical as defined above wherein at least one hydrogen radical is replaced with a hydroxyl radical, preferably 1-3 hydrogen radicals are replaced by hydroxyl radicals, more preferably 1-2 hydrogen radicals are replaced by hydroxyl radicals, and most preferably one hydrogen radical is replaced by a hydroxyl radical.
  • examples of such radicals include hydroxymethyl, 1-, 2-hydroxyethyl, 1-, 2-, 3 -hydroxypropyl , 1, 3 -dihydroxy-2-propyl, 1,3- dihydroxybutyl , 1,2,3,4,5, 6-hexahydroxy-2-hexyl and the like.
  • Alkenyl alone or in combination, means a straight- chain or branched-chain hydrocarbon radical having one or more double bonds, preferably 1-2 double bonds and more preferably one double bond, and containing preferably 2-15 carbon atoms (C 2 -C 15 ) , more preferably 2-8 carbon atoms (C2-C 8 ) , even more preferably 2-6 carbon atoms (C2-C6) yet more preferably 2-4 carbon atoms (C2-C4) and still more preferably 2-3 carbon atoms (C 2 -C3) .
  • alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4- butadienyl and the like.
  • Alkoxy alone or in combination, means a radical of the type "R-0-" wherein “R” is an alkyl radical as defined above and "0" is an oxygen atom.
  • alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy and the like.
  • Alkoxycarbonyl alone or in combination, means a radical of the type "R-O-C(O)-" wherein "R-0-" is an alkoxy radical as defined above and “C(O)” is a carbonyl radical .
  • Alkoxycarbonylamino alone or in combination, means a radical of the type “R-O-C (0) -NH-" wherein “R-O-C (0)” is an alkoxycarbonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
  • Alkylthio alone or in combination, means a radical of the type "R-S-" wherein "R” is an alkyl radical as defined above and “S” is a sulfur atom.
  • alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio and the like.
  • Alkylsulfinyl alone or in combination, means a radical of the type "R-S(O)-" wherein "R” is an alkyl radical as defined above and “S(0)” is a mono-oxygenated sulfur atom.
  • alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl and the like.
  • Alkylsulfonyl alone or in combination, means a radical of the type "R-S(0) 2 -" wherein "R” is an alkyl radical as defined above and “S(0) 2 " is a di-oxygenated sulfur atom.
  • alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl , n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.
  • Aryl alone or in combination, means a phenyl or biphenyl radical, which is optionally benzo fused or heterocyclo fused and which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, alkanoylamino, amido, amidino, alkoxycarbonylamino, N- alkylamidino, alkylamino, dialkylamino, aminoalkyl, alkylammoalkyl, dialkylammoalkyl, N-alkylamido, N,N- dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, oxo and the like.
  • aryl radicals are phenyl, o-tolyl, 4- methoxyphenyl, 2- (tert-butoxy) phenyl, 3-methyl-4- methoxyphenyl , 2-CF 3 -phenyl, 2-fluorophenyl, 2- chlorophenyl , 3-nitropheny1, 3 -aminophenyl , 3- acetamidophenyl, 2-amino-3- (aminomethyl) phenyl, 6- methyl-3-acetamidophenyl, 6-methyl-2-aminophenyl, 6- methyl-2 , 3 -diaminophenyl, 2-amino-3-methylphenyl, 4,6- dimethyl-2-aminophenyl, 4-hydroxyphenyl , 3-methyl-4- hydroxyphenyl , 4- (2-methoxyphenyl) phenyl, 2-amino-l- naphthyl, 2-naphthyl, 3-amino-2-naph
  • Alkyl and arylalkyl alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyl, 1-, 2- phenylethyl, dibenzylmethyl , hydroxyphenylmethyl, methylphenylmethyl , diphenylmethyl , dichlorophenylmethyl, 4-methoxyphenylmethyl and the like.
  • Alkoxy alone or in combination, means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyloxy, 1-, 2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy, methylphenylmethoxy, dichlorophenylmethoxy, 4- methoxyphenylmethoxy and the like.
  • Alkoxycarbonyl alone or in combination, means a radical of the type "R-O-C(O)-" wherein “R-0-” is an aralkoxy radical as defined above and “-C(O)-” is a carbonyl radical .
  • Alkanoyl alone or in combination, means a radical of the type "R-C(O)-" wherein "R” is an alkyl radical as defined above and "-C(O)-” is a carbonyl radical.
  • alkanoyl radicals include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
  • Alkanoylamino alone or in combination, means a radical of the type "R-C(0)-NH-" wherein "R-C(O)-" is an alkanoyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
  • aminocarbonyl alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
  • aminosulfonyl alone or in combination, means an amino substituted sulfonyl radical.
  • "Benzo fused” forms a ring system in which benzene and a cycloalkyl or aryl group have two carbons in common, for example tetrahydronaphthylene and the like.
  • Bicyclic as used herein is intended to include both fused ring systems, such as naphthyl and ⁇ -carbolinyl, and substituted ring systems, such as biphenyl, phenylpyridyl and diphenylpiperazinyl .
  • Cycloalkyl alone or in combination, means a saturated or partially saturated, preferably one double bond, monocyclic, bicyclic or tricyclic carbocyclic alkyl radical, preferably monocyclic, containing preferably 5- 12 carbon atoms (C5-C12) , more preferably 5-10 carbon atoms (C 5 -C 10 ) , even more preferably 5-7 carbon atoms
  • cycloalkyl radicals include cyclopentyl, cyclohexyl, dihydroxycyclohexyl, ethylenedioxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl , octahydroquinolinyl , dimethoxytetrahydronaphthyl , 2 , 3-dihydro-lH-indenyl , azabicyclo [3.2.1] octyl and the like.
  • Heteroatoms means nitrogen, oxygen and sulfur heteroatoms .
  • Heterocyclo fused forms a ring system in which a heterocyclyl or heteroaryl group of 5-6 ring members and a cycloalkyl or aryl group have two carbons in common, for example indole, isoquinoline, tetrahydroquinoline, methylenedioxybenzene and the like.
  • Heterocyclyl means a saturated or partially unsaturated, preferably one double bond, monocyclic or bicyclic, preferably monocyclic, heterocycle radical containing at least one, preferably 1 to 4, more preferably 1 to 3 , even more preferably 1-2, nitrogen, oxygen or sulfur atom ring member and having preferably 3-8 ring members in each ring, more preferably 5-8 ring members in each ring and even more preferably 5-6 ring members in each ring.
  • Heterocyclyl is intended to include sulfone and sulfoxide derivatives of sulfur ring members and N-oxides of tertiary nitrogen ring members, and carbocyclic fused, preferably 3-6 ring carbon atoms and more preferably 5-6 ring carbon atoms, and benzo fused ring systems.
  • Heterocyclyl radicals may optionally be substituted on at least one, preferably 1- 4, more preferably 1-3, even more preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, N- alkylamidino, alkoxycarbonylamino, alkylsulfonylamino and the like, and/or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals.
  • heterocyclyl is a radical of a monocyclic or bicyclic saturated heterocyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals.
  • heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl , 4-benzyl-piperazin-l-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidonyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl , tetrahydrothienyl and its sulfoxide and sulfone derivatives, 2 , 3-dihydroindolyl, tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydro-l- oxo-isoquinolinyl, 2 , 3-dihydrobenzofuryl, benzopyranyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like.
  • Heteroaryl means a monocyclic or bicyclic, preferably monocyclic, aromatic heterocycle radical, having at least one, preferably 1 to 4 , more preferably 1 to 3 , even more preferably 1-2, nitrogen, oxygen or sulfur atom ring members and having preferably 5-6 ring members in each ring, which is optionally saturated carbocyclic fused, preferably 3-4 carbon atoms (C 3 -C 4 ) to form 5-6 ring membered rings and which is optionally substituted as defined above with respect to the definitions of aryl .
  • heteroaryl groups include imidazolyl, l-benzyloxycarbonylimidazol-4-yl , pyrrolyl, pyrazolyl, pyridyl, 3- (2-methy1) yridyl, 3- (4- trifluoromethyl) pyridyl, pyrimidinyl, 5- (4- trifluoromethyl) pyrimidinyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, 5 , 6, 7 , 8-tetrahydroquinolyl,
  • Heteroaralkyl and “heteroarylalkyl, " alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above, such as 3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl, 2 -thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.
  • Halogen and halo alone or in combination, means fluoro, chloro, bromo or iodo radicals.
  • Haloalkyl alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals.
  • haloalkyl radicals include 1, 1, 1-trifluoroethyl, chloromethyl , 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bis (trifluoromethyl) methyl and the like.
  • “Pharmacologically acceptable salt” means a salt prepared by conventional means, and are well known by those skilled in the art.
  • the “pharmacologically acceptable salts” include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
  • cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like.
  • pharmaceutically acceptable salts see infra and Berge et al, J. Pharm . Sci . 66, 1 (1977) .
  • Cytokine means a secreted protein that affects the functions of other cells, particularly as it relates to the modulation of interactions between cells of the immune system or cells involved in the inflammatory response.
  • cytokines include but are not limited to interleukin 1 (IL-1) , preferably IL-l ⁇ , interleukin 6 (IL-6) , interleukin 8 (IL-8) and TNF, preferably TNF- ⁇ (tumor necrosis factor- ⁇ ) .
  • IL-1 interleukin 1
  • IL-6 interleukin 6
  • IL-8 interleukin 8
  • TNF preferably TNF- ⁇ (tumor necrosis factor- ⁇ ) .
  • TNF, IL-1, IL-6, and/or IL-8 mediated disease or disease state means all disease states wherein TNF, IL- 1, IL-6, and/or IL-8 plays a role, either directly as TNF, IL-1, IL-6, and/or IL-8 itself, or by TNF, IL-1, IL-6, and/or IL-8 inducing another cytokine to be released.
  • TNF a disease state in which IL-1 plays a major role, but in which the production of or action of IL-1 is a result of TNF, would be considered mediated by TNF.
  • leaving group generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art . Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate .
  • Protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.
  • aralkyl examples include, but are not limited to, benzyl, ortho- methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts .
  • aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9- ( 9-phenylfluorenyl ) , phenanthrenyl , durenyl and the like.
  • a mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group.
  • Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1, 2 -bis (methylene) benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings.
  • the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl .
  • Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • an addition salt such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups.
  • aralkyl groups .
  • Alkyl groups are also sutiable groups for protecting hydroxy and mercapto groups, such as tert- butyl .
  • Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups.
  • Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl , tert- butyldimethylsilyl, dimethylphenylsilyl , 1,2- bis (dimethylsilyl) benzene, 1, 2-bis (dimethylsilyl) ethane and diphenylmethylsilyl .
  • Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N,N, O-tri-silyl derivative.
  • silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium flouride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group.
  • Suitable silylating agents are, for example, trimethylsilyl chloride, tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF.
  • Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art.
  • Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
  • Prodrugs of the compounds of this invention are also contemplated by this invention.
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physicological action, such as hydrolysis, metabolism and the like, into a compound of this invention following adminstration of the prodrug to a patient.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985).
  • Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl) , cycloalkyl (for example, cyclohexyl) , aralkyl (for example, benzyl, p- methoxybenzyl ) , and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl) .
  • esters such as alkyl (for example, methyl, ethyl) , cycloalkyl (for example, cyclohexyl) , aralkyl (for example, benzyl, p- methoxybenzyl ) , and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl) .
  • Amines have been masked as arylcarbonyloxymethy1 substituted derivatives which are cleaved by esterases in vivo releasing the free drug and
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • Compounds according to the invention can be synthesized according to one or more of the following methods . It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R) . In addition, the compounds having one stereochemistry (e.g., (R) ) can often be utilized to produce those having opposite stereochemistry (i.e., (S) ) using well- known methods, for example, by inversion.
  • the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R) .
  • the compounds having one stereochemistry e.g., (R)
  • the disubstituted acrylic acid ester XII may be prepared conveniently by condensation of pyridine-4- carboxaldehyde with 4-fluorophenylacetic acid followed by esterification.
  • XII may be reacted with a variety of amidines V at elevated temperature.
  • sodium nitrite/acetic acid is suitable as a dehydrogenating agent for the conversion of XIII to II.
  • R 12 is any other heteroaryl ring within the definition of R 12 by the appropriate choice of starting material.
  • starting materials include but are not limited to 2-methylpyridine-4-carboxaldehyde, 2 , 6-dimethylpyridine-4-carboxaldehyde (Mathes and Sauermilch, Chem. Ber .
  • methyl 2- nitroisonicotinate (Stanonis, J. Org . Chem . 22, 475 (1957)) may be reacted with an aryl acetic acid ester followed by cyclization of the resultant b-keto ester with thiourea analogously to Scheme 3. Subsequent catalytic reduction of the nitro group to an amino group would give a pyrimidinone II in which R 12 is represented by a 2-amino-4-pyridyl group (Scheme 4) .
  • methyl 2-acetamido isonicotinate may be reacted analogously to Scheme 3 after appropriate protection of the amide nitrogen with e.g. a tert-butyldimethylsilyloxymethyl group (Benneche et al . , Acta Chem . Scand. B 42 384-389 (1988)), a fcert- butyldimethylsilyl group, a benzyloxymethyl group, a benzyl group or the like (P .
  • pyrimidinones II may be prepared by coupling a suitable derivative of XVIII (L is a leaving group, such as halogen radical and the like) with an appropriate aryl equivalent.
  • aryl/heteroaryl couplings are well known to those skilled in the art and involve an organic-metallic component for reaction with a reactive derivative, e.g., a halogeno derivative, of the second compound in the presence of a catalyst.
  • a reactive derivative e.g., a halogeno derivative
  • the metallo-organic species may be provided either by the pyrimidinone in which case the aryl component provides the reactive halogen equivalent or the pyrimidinone may be in the form of a reactive 5- halogeno derivative for reaction with a metallo organic aryl compound.
  • 5-bromo and 5-iodo derivatives of XVIII may be treated with arylalkyl tin compounds, e.g., trimethylstannylbenzene, in an inert solvent such as tetrahydrofuran in the presence of a palladium catalyst, such as di (triphenylphosphine) palladium (II) dichloride.
  • arylalkyl tin compounds e.g., trimethylstannylbenzene
  • an inert solvent such as tetrahydrofuran
  • a palladium catalyst such as di (triphenylphosphine) palladium (II) dichloride.
  • a palladium catalyst such as di (triphenylphosphine) palladium (II) dichloride.
  • 5-aryl-2 6-dipyridyl-4 (3ff) - pyrimidinones II may be prepared in a one step synthesis by reaction of the cyanopyridine with an arylacetyl ester, such as ethyl phenylacetate in the presence of sodium methoxide .
  • an arylacetyl ester such as ethyl phenylacetate
  • compounds of formula XXX can be readily prepared by reacting the methylsulfonyl intermediate XXXII with the amine NHR 5 R 21 , for example by heating the mixture preferably at a temperature greater than 40°C, more preferably 50-210°C.
  • Amines of formula NHR 5 R 21 are commercially available or can be readily prepared by those skilled in the art from commercially available starting materials.
  • an amide, nitro or cyano group can be reduced under reducing conditions, such as in the prescence of a reducing agent like lithium aluminum hydride and the like, to form the corresponding amine.
  • Alkylation and acylation of amino groups are well known in the art.
  • Chiral and achiral substituted amines can be prepared from chiral amino acids and amino acid amides (for example, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and the like substituted glycine, ⁇ -alanine and the like) using methods well known in the art, such as H. Brunner, P. Hankofer, U. Holzinger, B. Treittinger and H.
  • amino acid amides for example, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and the like substituted glycine, ⁇ -alanine and the like
  • pyridine-4-carboxaldehyde or other heteroaromatic carboxaldehyde-like pyrimidine- 4-carboxaldehydes or quinoline-4-carboxyaldehydes may be reacted with acetyl aryl, acetyl heteroaryl or acetyl cycloalkyl derivatives in the presence of piperidine/ acetic acid at elevated temperature (Bayer and Hartmann, Arch . Pharm .
  • XXIV may be reacted in a palladium or nickel catalyzed cross-coupling reaction with an alkyl or aryl boronic acid or an alkyl or aryl zinc halide to provide pyridone III wherein R 3 is alkyl or aryl or heteroaryl .
  • pyridone III may be substituted at the N-l position by reaction with, e.g., an alkyl halide in the presence of an appropriate base such as potassium carbonate .
  • Deprotection of the amine can be accomplished with acid treatment (p-toluenesulfonic acid) or tetrabutylammonium fluoride treatment.
  • the free amine can then be cyclized in an intramolecular fashion by warming to high temperatures .
  • the bromoalkylamines are either commercially available (eg. 3 -bromopropylamine hydrobromide , 2-bromoethylamine hydrobromide) or they can be synthesized from the corresponding haloalkylazide followed by reduction of the azide to the amine (see: Hendry et al Tetrahedron Lett 4597 (1987)).
  • More functionalized haloalkylamines can be used as long as the functional groups are tolerated in the transformations shown in scheme 12 including the bromo derivatives obtained from amino acid precursors as described by Robinson et al (Synlett. 51-53, 1993) and Leanna et al (Tetrahedron Lett. 4485, 1993) .
  • the fused ring system can be made through the addition of a hydroxyalkylamine as outlined in Scheme 14. Initially, the amine component of the hydroxyalkylamine displaces the 2-methylthio group to afford compound XXXVII which is followed by conversion of the alcohol to a suitable leaving group (eg. methanesulfonate or trifluoromethanesulfonate) . Closure of the ring can be accomplished by treatment with an excess of sodium hydride in DMF to afford XXXVI.
  • a suitable leaving group eg. methanesulfonate or trifluoromethanesulfonate
  • the 6,5 fused ring systems can be obtained as outlined in Scheme 15. Alkylation of the N-3 nitrogen with 3-bromo-l-trimethylsilylpropyne can be followed by a displacement of the 2-methylthio group with the appropriate amine component exemplified but not limited to a phenylalkylamine .
  • the 2 -amino group under the reaction conditions cyclizes onto the acetylene as shown with a loss of the trimethylsilyl group as well.
  • Rl (CH 3 ) 2 CH-
  • R 1 CH 3 (CH 2 ) 3 NH-
  • R 1 CH 3 (CH 2 ) 4 NH-
  • R 1 H 2-32 2-( (2,2-dimethyl-3-hvdro ⁇ ypropyl) -amino) -5- (4- fluorophenyl) -3 -methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone:
  • Step A 5- (4-Fluorophenyl) -3-methyl-2-methylthio-6- (4- (2 -acetamido) pyridyl ) ) -4 ( 3ff) -pyrimidinone : To a solution of 5- (4-fluorophenyl) -6- (4- (2- aceta ido) pyridyl) -2-thiouracil (600 mg, 1.68 mmol) in DMF (35 L) was added powdered sodium hydride (60% oil dispersion, 221 mg, 5.56 mmol) over 1 minute at 23°C After 45 min, iodomethane (210 ml, 3.37 mmol) was added dropwise.
  • reaction was concentrated in vacuo (rotovap connected to high vac with a bath temperature no greater than 40°C) .
  • residue was applied immediately to flash chromatography purification (step gradient hexane: acetone 4:1; then 3:1; then 2:1; the 1:1) to afford the desired product.
  • Step B 5- (4-Fluorophenyl) -3-methyl-2- ( (3-phenylpropyl) - amino) -6- (4- (2-amino) pyridyl) ) -4 (3ff) -pyrimidinone: A neat mixture of 5- (4-Fluorophenyl) -3-methyl-2- methylthio-6- (4- (2-acetamido) pyridyl) ) -4 (3H) - pyrimidinone (50 mg, 0.13 mmol) and 3-phenyl-l- propylamine (88 mg, 0.65 mmol) was warmed to 190°C for 17 h.
  • R 31 C ( 0) CH 2 OAc
  • R 32 H
  • R 31 CH 2 Ph 4-7 5- (4-Fluorophenyl) -3-methyl-2- ( ( 3-phenylpropyl ) - amino)-6-(4-(2-(2-methoxyphenyl ) methylamino) pyridyl ) ) - 4 (3ff) -pyrimidinone : The reaction was done in the manner of the above substituting 2 -methoxybenzaldehyde for benzaldehyde to afford the title compound after chromatography: MS (m/z) 550 (M+H) + .
  • R H
  • R NH(CO)NHMe 4-13 5- (4-Fluorophenyl) -3-methyl-2- ( ( 3 -phenylpropyl ) - amino) -6-(4-(2-(2' amino-1 ' -oxo-ethylamino) pyridyl) ) - 4 ( 3ff) -pyrimidinone : General Procedure for mixed anhydride coupling - Isobutyl chloroformate (32 ml, 0.24 mmol) was added dropwise to a -20-30 oC solution of N-a- t-Boc-glycine (5.6 mg, 0.05 mmol) and pyridine (0.6 mL) .
  • the reaction mixture was applied to purification via flash chromatography (step gradient l%Me0H:CHC13 then 2%%, then 3%; then 4%; then 5%) to afford the N-Boc protected title compound.
  • the crude title compound was obtained after treatment with 50% trifluoroacetic acid: chloroform (1 mL) for 16 h. After concentration with a stream of nitrogen, the reaction mixture was applied to purification via flash chromatography (step gradient l%MeOH:CHC13 then 2%, then 3%; then 4%; then 5%) to afford the title compound: MS (m/z) : 487 (M+H) + .
  • R 32 H 4-17 2- ( ( (S) -2-Dimethylamino-3-phenylpropyl) -amino) -5-
  • reaction mixture was applied directly to purification via flash chromatography (step gradient l%MeOH:CHCl3 then 2%, then 3%; then 4%; then 5%) to afford 5- (4-Fluorophenyl) -3- methyl-2- (phenylmethylamino) -6- (4- (2-amino) pyridyl) ) - 4 (3ff) -pyrimidinone.
  • Step A 5- (4-Fluorophenyl) -2-methylthio-6- (4-pyridyl) -
  • (S) -1, 2-Benzylethylendiamine The diamine was prepared according to the literature (H. Brunner, P. Hankofer, U. Holzinger, B. Treittinger and H. Schoenenberger, Eur. J. Med. Chem. 25, 35-44, (1990)) by reduction of L- phenylalanine amide with lithium aluminium hydride.
  • the (R) -enantiomer was prepared in the same manner from D- phenylalanine amide.
  • Step A 5- (4-Fluorophenyl) -3-methyl-2-methylsulfonyl-6- (4-pyridyl) -4 (3H) -pyrimidinone: A mixture of 5- (4- fluorophenyl) -3-methyl-2-methylthio-6- (4-pyridyl) -4 (3H) - pyrimidinone (400 mg, 1.22 mmol) and Oxone" (potassium peroxymonosulfate, 2.3 g, 3.74 mmol) in methanol (100 ml) and water (45 ml) was stirred for 13 h. The solvent was concentrated to about 50 ml, followed by extraction with dichloromethane, drying of the organic solution and evaporation. The resulting white solid was used without purification in the next step.
  • Step B 2- ( ( (S) -2-N,N-Dimethylamino-3-phenylpropyl) - amino) -5- (4-fluorophenyl-3 -methyl-6- (4-pyridyl) -4 (3H) - pyrimidinone hydrochloride: A mixture of crude 5- (4- fluorophenyl) -3-methyl-2-methylsulfonyl-6- (4-pyridyl) - 4 (3H) -pyrimidinone (430 mg g, 1.19 mmol) and ( S ) -2-N, N- dimethylamino-3-phenylpropylamine (600 mml, -3.4 mmol) was stirred at room temperature for lh and then briefly o warmed at 50 C.
  • Example 20 5- (4- fluorophenyl ) -6- (4- (2-acetamido) -pyridyl ) -2- thioalkyl -4 (3H) -pyrimidinone s Step A. Ethyl 2- (4-fluorophenyl) -3-oxo-3- (4- (2- acetamido) -pyridyl) ) -propionate: A solution of 2-chloroisonicotinic acid (25. Og, 0.16 mol) in 65 mL of concentrated ammonium hydroxide was warmed to 205 Celsius in a steel bomb for 72 h.
  • the solution was acidified to a pH of 1 using 6N HCl and subsequently filtered to remove unreacted starting material.
  • the solution was concentrated to one fourth the original volume (approx 200 mL) in vacuo, and carefully adjusted to a pH of 6 using 1 N NaOH.
  • the desired 2-aminoisonicotinic acid was filtered off.
  • To a suspension of 2-aminoisonicotinic acid in ethanol (600 mL) was added 47.1 mL of 4 N anhdrous HCl in dioxane.
  • Step B 5- (4-fluorophenyl) -6- (4- (2-acetamido) yridyl) ) -
  • 2-Methyl-3 -phenylpropylamine A mixture of commercially available 2-methyl-3 -phenylpropylamide (4.32 g, 26.5 mmol) and lithium aluminium hydride (1.3 g, 34.3 mmol) in tetrahydrofuran (184 ml) was stirred at room temperature for 5 h. It was poured into aqu. sat. sodium sulfate and extracted with dichloromethane followed by drying of the organic solution and evaporation to provide the amine as an oil. Other syntheses have been reported, e.g. Dornow and Fust, Chem. Ber. 87, 984 (1954).
  • Step A Methyl 2-amino-3- (2-fluorophenyl) ropionate : 5g (27.3 mmol) of (D, L) - (2-fluoro-phenyl) alanine was suspended in 50 ml methanolic HCl and stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and dried to give a yellow oil. MS (m/z): 198 (M+H) + ; C 10 H 12 FNO 2 requir. 197.2.
  • Step B 2-Amino-3- (2-fluorophenyl)propionamide : Methyl 2-amino-3- (2-fluorophenyl) propionate was suspended in 50 ml 30% ammonium hydroxide and stirred at room temperature for 18 hrs . The mixture was filtered, washed with cold water and 2-amino-3- (2-fluorophenyl) propionamide was collected as a white solid. MS (m/z) : 183.1 (M+H) + ; C-H ⁇ FN j O requir. 182.2.
  • borane-methyl sulfide complex (2N, 3 ml, 6 mmol) was added dropwise to a solution of the nitrile (1 g, 4.06 mmol) in tetrahydrofuran (6 ml). Methyl sulfide was distilled off and the resulting solution refluxed for 2.5 h. With ice-cooling, methanolic hydrogen chloride (IN, 3 ml) was added followed by evaporation. The remainder was taken up in methanol (10 ml) and 4N hydrogen chloride/dioxane (10 ml) was added.
  • Step A Methyl (2S, 3R, ⁇ S) -3- (N-benzyl -N- ⁇ - methylbenzylamino) -2-methyl-3 -phenylpropionate was prepared as reported for the 2R, 3S, ⁇ R-enantiomer (S.G.
  • Step B Methyl (2S , 3R) -3 -amino-2-methyl-3- phenylpropionate : A mixturte of methyl (2S, 3R, S) -3- (N-benzyl -N-a-methylbenzylamino) -2-methyl-3- phenylpropionate (13.0 g, 33.55 mmol) and 10% palladium- on-carbon (13.0 g) in glacial acetic acid (260 ml) was hydrogenated under a balloon of hydrogen for 24 h. The catalyst was removed by filtration followed by evaporation and co-distillation with toluene to provide the title compound as a white solid. MS (m/z) : 194.2 (M+H) + ; C ⁇ H ⁇ NO. requir. 193.3.
  • Step D (2R, 3R) -2-methyl-3 -phenyl-1 , 3-propanediamine: Lithium aluminium hydride (2.3 g, 60.60 mmol) was added in portions to a stirring solution of (2S, 3R) -3-amino-2- methyl-3-phenylpropionamide (2.6 g, 14.59 mmol) in tetrahydrofuran (54 ml) at ice-bath temperature. After 45 min, the mixture was heated at reflux for 16 h. With ice-bath cooling, the reaction was quenched by the portionwise addition of sodium sulfate decahydrate and some methanol until hydrogen evolution ceased. The solids were removed by filtration and washed with dichloromethane. The combined filtrates were evaporated to provide the title compound. MS (m/z) : 165.2 (M+H) + ; C 10 H 16 N 2 requir. 164.3.
  • the enantiomer (2S, 3S) -2-methyl-3 -phenyl- 1 , 3 -propanediamine was prepared from methyl (2R,3S, ⁇ R)- 3- (N-benzyl -N- ⁇ -methylbenzylamino) -2-methyl-3- phenylpropionate.
  • MS (m/z) 165.3 (M+H) + ; C 10 H 16 ⁇ 2 requir . 164.3.
  • the enantiomers (2R, 3S) -2-methyl-3- ⁇ henyl- 1 , 3 -propanediamine and (2S, 3R) -2-methyl-3 -phenyl-1 , 3- propanediamine may be prepared from tert.butyl
  • Step B 2- ( (S) -3-Benzylpiperaziny) -5- (4-fluorophenyl) -3- methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride: A mixture of crude 5- (4-fluorophenyl) -3 -methyl-2- methylsulfonyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (434 mg, 1.21 mmol) and (S) -2-benzylpiperazine (426 mg, 2.42 mmol) was heated at 105°C for 1 h.
  • the resulting material was converted into its hydrochloride by the addition of 4N hydrogen chloride/dioxane (75 ⁇ l) to its methanolic solution (3 ml) followed by evaporation.
  • MS (m/z) 456.5 (M+H) + ; C 27 H 26 FN 5 0 requir. 455.5(free base).
  • Step A 5- (4-Fluorophenyl) -2- (4-phenylbutyl) -6- (4- pyridyl) -4 (3H) -pyrimidinone: Ethyl 2- (4-fluorophenyl) - 3-oxo-3- (4-pyridyl) -propionate (293 mg, 1.02 mmol), 4- phenylbutanecarboxamidine (315 mg, 1.79 mmol) and pyridinium p-toluenesulfonate (10 mg) were suspended in p-xylene (10 ml) . With efficient stirring, the mixture was heated to reflux using a Dean-Stark apparatus with continuous removal of water.
  • Step B 5- (4-Fluorophenyl) -3-methyl-2- (4-phenylbutyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone : Methyl iodide (22 ⁇ l, 0.351 mmol) was added to a stirring mixture of 5- (4- fluorophenyl) -2- (4-phenylbutyl) -6- (4-pyridyl) -4 (3H) - pyrimidinone (140 mg, 0.351 mmol) and potassium carbonate (49 mg, 0.351 mmol) in N, N-dimethylformamide (5 ml) .
  • Step A 6- (4-pyridyl) -2-thiouracil: Ethyl isonicotinoylacetate (5g, 25.89 mmol) and thiourea (5.94 g, 77.64 mmol) were suspended in anhydrous p-xylene (100ml) with vigorous stirring. To the mixture, pyridinium p-toluenesulfonate (150mg) was added and refluxed for 12-16 h using a Dean-Stark apparatus with continuous removal of water (0.5ml). The reaction mixture was cooled and a dark brown solid was filtered. The collected solid was suspended in acetone (25 ml) and filtered.
  • Step B 3-Methyl-6- (4-pyridyl) -2-methylthio-4 (3H)- pyrimidinone: 6- (4-Pyridyl) -2-thiouracil (1.5g 7.299 mmol) was dissolved in DMF (50 ml) and the mixture was cooled to 0°C. Sodium hydride (0.437 g, 0.730g 60% in oil, 18.25 mmol) was added and the reaction mixture was stirred for 30 minutes. Methyl iodide (1.2 ml, 2.6g, 18.25 mmol) was added dropwise over 15 minutes. Formation of dimethyl compound was monitored by TLC .
  • Tetrakis triphenyl phosphine Pd(0) 350 mg was added. The reaction mixture was refluxed for 8-12h. The formation of the product was monitored by TLC . The mixture was cooled, diluted with toluene (20ml) and washed with water. The organic layer was dried over sodium sulfate, concentrated and product isolated by silica gel chromatgraphy to give the titled compoud. MS (m/z): 378.4 C 18 H 14 F 3 N 3 OS requir.
  • Step E 3-methyl-2- (2 (S) -amino-3 -phenylpropylamino) -5- (3 -trifluoromethylphenyl) -6- (4-pyridyl) -4 (3H) - pyrimidinone : 3-Methyl-5- (3-trifluoromethylphenyl) -6- (4- pyridyl) -2-thiomethyl-4 (3H) -pyrimidinone (0.7g, 1.85 mmol) and (S) -2-amino-3 -phenyl-1-propylamine (0.9 ml,
  • Step A 3-Methyl-5- (3-methylphenyl) -6- (4-pyridyl) -
  • Step B 2 -Chloro-3 -methyl-5- (3-methylphenyl) -6- (4- pyridyl) -4 (3H) -pyrimidinone: A mixture of 3-methyl-5- ( 3 -methylphenyl ) -6- (4-pyridyl) -2, 4 (IH, 3H) -pyrimidindione (12.5 g, 0.043 mol) and phosphorus oxychloride (65 ml) was refluxed for 16 h. The excess of phosphorus oxychloride was evaporated followed by co-distillation with toluene. The remainder was carefully partitioned between dichloromethane and aqueous sodium hydrogencarbonate. The organic solution was washed with water, dried and evaporated to leave the title compound. MS (m/z) : 312 (M) + ; C 17 H 14 CIN 3 O requir. 311.8.
EP97951678A 1996-12-05 1997-12-04 Substituted pyrimidinone and pyridone compounds and methods of use Withdrawn EP0948496A2 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US3212896P 1996-12-05 1996-12-05
US32128P 1996-12-05
US5095097P 1997-06-13 1997-06-13
US50950P 1997-06-13
US97605397A 1997-11-21 1997-11-21
US976053 1997-11-21
PCT/US1997/022949 WO1998024780A2 (en) 1996-12-05 1997-12-04 Substituted pyrimidinone and pyridinone compounds and their use

Publications (1)

Publication Number Publication Date
EP0948496A2 true EP0948496A2 (en) 1999-10-13

Family

ID=27364029

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97951678A Withdrawn EP0948496A2 (en) 1996-12-05 1997-12-04 Substituted pyrimidinone and pyridone compounds and methods of use

Country Status (13)

Country Link
EP (1) EP0948496A2 (pt)
JP (1) JP2002514196A (pt)
KR (1) KR100476586B1 (pt)
CN (1) CN1328277C (pt)
AU (1) AU735901C (pt)
BG (1) BG65129B1 (pt)
BR (1) BR9713863A (pt)
CA (1) CA2274093C (pt)
CZ (1) CZ9902016A3 (pt)
HU (1) HUP0001140A3 (pt)
IL (1) IL130181A0 (pt)
NZ (1) NZ335992A (pt)
WO (1) WO1998024780A2 (pt)

Families Citing this family (94)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6410729B1 (en) * 1996-12-05 2002-06-25 Amgen Inc. Substituted pyrimidine compounds and methods of use
US6613942B1 (en) 1997-07-01 2003-09-02 Novo Nordisk A/S Glucagon antagonists/inverse agonists
WO1999032121A1 (en) 1997-12-19 1999-07-01 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositions and uses
US6858617B2 (en) 1998-05-26 2005-02-22 Smithkline Beecham Corporation Substituted imidazole compounds
TWI241298B (en) * 1998-09-25 2005-10-11 Mitsubishi Chem Corp Pyrimidone derivatives
AU1909200A (en) 1998-11-04 2000-05-22 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
GB9910378D0 (en) * 1999-05-05 1999-06-30 Smithkline Beecham Plc Novel compounds
US6503949B1 (en) 1999-05-17 2003-01-07 Noro Nordisk A/S Glucagon antagonists/inverse agonists
US6403596B1 (en) 1999-06-28 2002-06-11 Merck & Co., Inc. Substituted pyridones having cytokine inhibitory activity
DE60020595T2 (de) 1999-11-23 2006-03-16 Smithkline Beecham Corp. 3,4-dihydro-(1h)chinazolin-2-on-verbindungen als csbp/p38-kinase-inhibitoren
US6759410B1 (en) 1999-11-23 2004-07-06 Smithline Beecham Corporation 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors
ATE305787T1 (de) 1999-11-23 2005-10-15 Smithkline Beecham Corp 3,4-dihydro-(1h)chinazolin-2-on-verbindungen als csbp/p39-kinase-inhibitoren
EP1136482A1 (en) 2000-03-23 2001-09-26 Sanofi-Synthelabo 2-Amino-3-(alkyl)-pyrimidone derivatives as GSK3beta inhibitors
JP2005289808A (ja) * 2000-03-23 2005-10-20 Sanofi-Aventis ３−置換−４−ピリミドン誘導体
EP1136099A1 (en) * 2000-03-23 2001-09-26 Sanofi-Synthelabo 2-(Indolylalkylamino)pyrimidone derivatives as GSK3beta inhibitors
EP1136493A1 (en) * 2000-03-23 2001-09-26 Sanofi-Synthelabo 2-(Thienopyridinyl)pyrimidone, 2-(furopyridinyl)pyrimidone 2-(isoquinolinyl)pyrimidone, 2-(pyridoindolyl)pyrimidone and 2-(benzofuropyridinyl)pyrimidone derivatives
US7189717B2 (en) 2000-04-26 2007-03-13 Eisai Co., Ltd. Medicinal compositions promoting bowel movement
NZ522773A (en) 2000-06-12 2005-06-24 Eisai Co Ltd 1,2-dihydropyridine compounds, manufacturing method thereof and use thereof
US7115608B2 (en) * 2000-09-19 2006-10-03 Centre National De La Recherche Schentifique Pyridinone and pyridinethione derivatives having HIV inhibiting properties
GB0024808D0 (en) * 2000-10-10 2000-11-22 Smithkline Beecham Plc Novel compounds
AU2002223500A1 (en) 2000-11-17 2002-05-27 Novo-Nordisk A/S Glucagon antagonists/inverse agonists
US6706744B2 (en) 2000-11-17 2004-03-16 Novo Nordisk A/S Glucagon antagonists/inverse agonists
US6821960B2 (en) 2000-11-17 2004-11-23 Noyo Nordisk Pharmaceuticals, Inc. Glucagon antagonists/inverse agonists
PT1674456E (pt) 2001-09-21 2008-09-11 Sanofi Aventis Utilização de 2-fluoro-3-cetoésteres para preparar 3-fluoro- 6,7,8,9-tetra-hidro-4-h-pirimido[1,2-a]pirimidin-4-onas
EP1295885A1 (en) * 2001-09-21 2003-03-26 Sanofi-Synthelabo Substituted 2-pyridinyl-6,7,8,9-tetrahydropyrimido(1,2-a)pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo(1,2-a)pyrimidin-5(1H)one derivatives
EP1295884A1 (en) * 2001-09-21 2003-03-26 Sanofi-Synthelabo 2-pyrimidinyl-6,7,8,9-tetrahydropyrimido[1,2-a]Pyrimidin-4-one and 7-Pyrimidinyl-2,3-Dihydroimidazo[1,2-a]Pyrimidin-5(1H)one derivatives
AU2002337498B2 (en) 2001-09-21 2006-08-10 Mitsubishi Pharma Corporation 3-substituted-4-pyrimidone derivatives
EP1430056B1 (en) 2001-09-21 2005-10-26 Sanofi-Aventis Substituted 2-pyrimidinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyrimidinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1h)one derivatives for neurodegenerative disorders
TWI301834B (en) * 2001-10-22 2008-10-11 Eisai R&D Man Co Ltd Pyrimidone compound and pharmaceutical composition including the same
TWI330183B (pt) * 2001-10-22 2010-09-11 Eisai R&D Man Co Ltd
US6921762B2 (en) 2001-11-16 2005-07-26 Amgen Inc. Substituted indolizine-like compounds and methods of use
US6881746B2 (en) 2001-12-03 2005-04-19 Novo Nordick A/S Glucagon antagonists/inverse agonists
US6762318B2 (en) 2001-12-03 2004-07-13 Novo Nordisk A/S Glucagon antagonists
EP1458717B1 (en) * 2001-12-21 2005-09-07 Bayer HealthCare AG Aroyl pyridinones
AU2003216591A1 (en) * 2002-04-10 2003-10-20 Orichid Chemicals And Pharmaceuticals Limited Amino substituted pyrimidinone derivatives useful in the treatment of inflammation and immunological
CA2485166A1 (en) 2002-05-21 2003-12-04 Amgen Inc. Substituted pyrimidinone and pyridinone compounds
WO2004004725A2 (en) 2002-07-09 2004-01-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases
US7683069B2 (en) 2002-12-16 2010-03-23 Mitsubishi Tanabe Pharma Corporation 3-substituted-4-pyrimidone derivatives
TWI357408B (en) 2003-03-26 2012-02-01 Mitsubishi Tanabe Pharma Corp 3-substituted-4-pyrimidone derivatives
US20070167621A1 (en) 2003-04-03 2007-07-19 Pharmacia Corporation Substituted pyrimidinones
US7183287B2 (en) * 2003-04-03 2007-02-27 Pharmacia Corporation Substituted pyrimidinones
CA2533684A1 (en) * 2003-07-25 2005-02-10 Amgen Inc. Substituted pyridones and pyrimidinones with antiinflammatory properties
RU2006107553A (ru) * 2003-08-13 2007-09-20 Такеда Фармасьютикал Компани Лимитед (Jp) Производные 4-пиримидона и их применение в качестве ингибиторов пептидилпептидаз
US7429594B2 (en) 2003-08-20 2008-09-30 Amgen Inc. Substituted heterocyclic compounds and methods of use
SE0302486D0 (sv) 2003-09-18 2003-09-18 Astrazeneca Ab Novel compounds
EP1557417B1 (en) * 2003-12-19 2007-03-07 Sanofi-Aventis Substituted 8'-pyri(mi)dinyl-dihydrospiro-[cycloalkylamine]-pyrimido[1,2-a] pyrimidin-6-one derivatives
US20060035893A1 (en) 2004-08-07 2006-02-16 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
GB0420722D0 (en) 2004-09-17 2004-10-20 Addex Pharmaceuticals Sa Novel allosteric modulators
EP2708531A1 (en) 2004-10-13 2014-03-19 Pharmacia & Upjohn Company LLC Crystalline Forms Of 3-[5-Chloro-4-[(2,4-difluorobenzyl) oxy]-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide
MX2007007330A (es) 2004-12-16 2007-10-04 Vertex Pharma Piridonas de utilidad como inhibidores de quinasas .
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
NZ566799A (en) 2005-09-14 2011-04-29 Takeda Pharmaceutical Dipeptidyl peptidase inhibitors for treating diabetes
CN101360723A (zh) 2005-09-16 2009-02-04 武田药品工业株式会社 制备嘧啶二酮衍生物的方法
AR059898A1 (es) 2006-03-15 2008-05-07 Janssen Pharmaceutica Nv Derivados de 3-ciano-piridona 1,4-disustituida y su uso como moduladores alostericos de los receptores mglur2
TW200808763A (en) 2006-05-08 2008-02-16 Astrazeneca Ab Novel compounds I
TW200808771A (en) 2006-05-08 2008-02-16 Astrazeneca Ab Novel compounds II
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
WO2008104752A1 (en) * 2007-02-26 2008-09-04 Astrazeneca Ab Dihydropyridones as elastase inhibitors
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
EP1992344A1 (en) 2007-05-18 2008-11-19 Institut Curie P38 alpha as a therapeutic target in pathologies linked to FGFR3 mutation
KR20100065191A (ko) 2007-09-14 2010-06-15 오르토-맥닐-얀센 파마슈티칼스 인코포레이티드 １,３-이치환된 ４-(아릴-ｘ-페닐)-１ｈ-피리딘-２-온
CN101801951B (zh) 2007-09-14 2013-11-13 杨森制药有限公司 1’,3’-二取代的-4-苯基-3,4,5,6-四氢-2h,1’h-[1,4’]二吡啶-2’-酮
CL2008003301A1 (es) 2007-11-06 2009-10-16 Astrazeneca Ab Compuestos derivados de 3,4-dihidropirazina-2-carboxamida, inhibidores de la elastasa de neutrofilos humanos; composiciones farmacéuticas; procesos de preparación de compuestos y composición farmacéutica; y uso en el tratamiento de síndrome de dificultad respiratoria de los adultos, fibrosis quística, cáncer, entre otras.
RU2510396C2 (ru) 2008-09-02 2014-03-27 Янссен Фармасьютикалз, Инк. 3-азабицикло[3.1.0]гексильные производные в качестве модуляторов метаботропных глутаматных рецепторов
CA2741666C (en) * 2008-10-31 2017-04-11 Merck Sharp & Dohme Corp. P2x3, receptor antagonists for treatment of pain
AU2009319387B2 (en) 2008-11-28 2012-05-10 Addex Pharma S.A. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
TW201036957A (en) 2009-02-20 2010-10-16 Astrazeneca Ab Novel salt 628
JP5707390B2 (ja) 2009-05-12 2015-04-30 ジャンセン ファーマシューティカルズ， インコーポレイテッド １，２，４−トリアゾロ［４，３−ａ］ピリジン誘導体およびｍＧｌｕＲ２受容体の正のアロステリック調節因子としてのその使用
RS53075B (en) 2009-05-12 2014-04-30 Janssen Pharmaceuticals Inc. 1,2,4-TRIAZOLO [4,3-A] PYRIDINE DERIVATIVES AND THEIR USE IN THE TREATMENT OR PREVENTION OF NEUROLOGICAL AND PSYCHIATRIC DISORDERS
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
WO2011039528A1 (en) 2009-10-02 2011-04-07 Astrazeneca Ab 2-pyridone compounds used as inhibitors of neutrophil elastase
EP2643320B1 (en) 2010-11-08 2015-03-04 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
EP2649069B1 (en) 2010-11-08 2015-08-26 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
EP2661435B1 (en) 2010-11-08 2015-08-19 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
BR112013016033A2 (pt) 2010-12-23 2018-06-05 Pfizer moduladores do receptor de glucagon
IL227559A (en) 2011-02-08 2016-04-21 Pfizer Glucagon receptor modulator
ES2543050T3 (es) 2011-02-28 2015-08-14 Array Biopharma, Inc. Inhibidores de serina/treonina quinasa
WO2013014569A1 (en) 2011-07-22 2013-01-31 Pfizer Inc. Quinolinyl glucagon receptor modulators
US9187462B2 (en) 2011-08-04 2015-11-17 Array Biopharma Inc. Substituted quinazolines as serine/threonine kinase inhibitors
CA2853024C (en) 2011-11-11 2017-08-22 Pfizer Inc. 2-thiopyrimidinones
CN103130787B (zh) * 2011-11-24 2015-06-10 南开大学 嘧啶酮酰胺类化合物及其制备方法、抗hiv活性和抗tmv活性
SI2820009T1 (en) 2012-03-01 2018-05-31 Array Biopharma, Inc. Serine / Threonine kinase inhibitors
BR112015004548A2 (pt) 2012-08-27 2017-08-08 Array Biopharma Inc inibidores de serina/treonina para tratamento de doenças hiperproliferativas
JO3368B1 (ar) 2013-06-04 2019-03-13 Janssen Pharmaceutica Nv مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2
JO3367B1 (ar) 2013-09-06 2019-03-13 Janssen Pharmaceutica Nv مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2
ES2860298T3 (es) 2014-01-21 2021-10-04 Janssen Pharmaceutica Nv Combinaciones que comprenden moduladores alostéricos positivos del receptor glutamatérgico metabotrópico de subtipo 2 y su uso
DK3431106T3 (da) 2014-01-21 2021-03-15 Janssen Pharmaceutica Nv Kombinationer omfattende positive allosteriske modulatorer eller orthosteriske agonister af metabotrop glutamaterg subtype 2-receptor og anvendelse af disse
KR101693781B1 (ko) * 2014-10-06 2017-01-09 한양대학교 에리카산학협력단 다이플루오로알킬기가 도입된 방향족 화합물의 제조 방법
EP3292109A1 (en) 2015-05-05 2018-03-14 Pfizer Inc 2-thiopyrimidinones
CN107200731B (zh) * 2017-06-11 2020-10-23 湖南科技大学 一种含噻唑环吡啶酮衍生物及其制备方法和应用
CN110078674B (zh) * 2019-04-10 2022-11-01 昆明理工大学 一种2-烃基胺基嘧啶酮的制备方法
JOP20220125A1 (ar) 2019-11-25 2023-01-30 Amgen Inc مركبات حلقية غير متجانسة على هيئة مثبطات دلتا-5 ديساتوراز وطرق لاستخدامها
CN115650906A (zh) * 2022-11-04 2023-01-31 苏州艾缇克药物化学有限公司 一种2-氨基异烟酸的制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1271116B (de) * 1965-05-04 1968-06-27 Bayer Ag Verfahren zur Herstellung von 4-Hydroxypyrimidinen
JPS6163680A (ja) * 1984-09-05 1986-04-01 Kanto Ishi Pharma Co Ltd ピリミド〔１，２−ａ〕ベンズイミダゾ−ル誘導体及びその製造方法
US5620999A (en) * 1994-07-28 1997-04-15 Weier; Richard M. Benzenesulfonamide subtituted imidazolyl compounds for the treatment of inflammation
IL123950A (en) * 1995-10-06 2001-04-30 Merck & Co Inc Transformed imidazoles with anti-cancer and cytokine-inhibiting activity and pharmaceutical preparations containing them
WO1997016442A1 (en) * 1995-10-31 1997-05-09 Merck & Co., Inc. Substituted pyridyl pyrroles, compositions containing such compounds and methods of use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9824780A3 *

Also Published As

Publication number Publication date
AU5525498A (en) 1998-06-29
CN1328277C (zh) 2007-07-25
IL130181A0 (en) 2000-06-01
KR20000069329A (ko) 2000-11-25
WO1998024780A3 (en) 1998-07-30
HUP0001140A3 (en) 2002-05-28
CZ9902016A3 (cs) 1999-11-17
CN1246857A (zh) 2000-03-08
KR100476586B1 (ko) 2005-03-18
WO1998024780A2 (en) 1998-06-11
AU735901B2 (en) 2001-07-19
CA2274093A1 (en) 1998-06-11
BG103521A (en) 2000-07-31
NZ335992A (en) 2001-09-28
BG65129B1 (bg) 2007-03-30
JP2002514196A (ja) 2002-05-14
HUP0001140A2 (hu) 2001-04-28
BR9713863A (pt) 2000-03-14
CA2274093C (en) 2006-11-07
AU735901C (en) 2004-02-12

Similar Documents

Publication Publication Date Title
AU735901C (en) Substituted pyrimidinone and pyridone compounds and methods of use
US6420385B1 (en) Substituted pyrimidinone and pyridone compounds and methods of use
US6610698B2 (en) Substituted pyrimidine compounds and methods of use
AU755421B2 (en) Substituted pyridine and pyridazine compounds and their pharmaceutical use
WO1998024782A2 (en) Substituted pyrimidine compounds and their use
US6174901B1 (en) Substituted pyridine and pyridazine compounds and methods of use
US6605634B2 (en) Aryl and heteroaryl substituted fused pyrrole anti-inflammatory agents
EP1448564A2 (en) Substituted indolizine-like compounds and methods of use
WO1998022457A9 (en) Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
AU733877C (en) Substituted pyrimidine compounds and their use
AU8142901A (en) Substituted pyrimidinone and pyridone compounds and methods of use
EP1314732A2 (en) Substituted pyrimidine compounds and their use
MXPA99005168A (en) Substituted pyrimidine compounds and their use
KR20000069328A (ko) 치환된 피리미딘 화합물과 그것의 용도

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19990607

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 19990607;LT PAYMENT 19990607;LV PAYMENT 19990607;MK PAYMENT 19990607;RO PAYMENT 19990607;SI PAYMENT 19990607

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: AMGEN INC.

17Q First examination report despatched

Effective date: 20040526

R17C First examination report despatched (corrected)

Effective date: 20040526

17Q First examination report despatched

Effective date: 20040526

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/505 20060101ALI20090129BHEP

Ipc: A61K 31/44 20060101ALI20090129BHEP

Ipc: C07D 487/04 20060101ALI20090129BHEP

Ipc: C07D 409/14 20060101ALI20090129BHEP

Ipc: C07D 409/12 20060101ALI20090129BHEP

Ipc: C07D 405/04 20060101ALI20090129BHEP

Ipc: C07D 403/12 20060101ALI20090129BHEP

Ipc: C07D 403/04 20060101ALI20090129BHEP

Ipc: C07D 401/14 20060101ALI20090129BHEP

Ipc: C07D 401/04 20060101AFI20090129BHEP

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1020196

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090623